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Novel insight into the lipid network of plasma extracellular vesicles reveal sex-based differences in the lipidomic profile of alcohol use disorder patients 对血浆细胞外囊泡脂质网络的新认识揭示了酒精使用障碍患者脂质组学特征的性别差异
IF 7.9 2区 医学 Q1 Social Sciences Pub Date : 2024-01-25 DOI: 10.1186/s13293-024-00584-5
Carla Perpiñá-Clérigues, Susana Mellado, Cristina Galiana-Roselló, María Fernández-Regueras, Miguel Marcos, Francisco García-García, María Pascual
Alcohol use disorder (AUD) is one of the most common psychiatric disorders, with the consumption of alcohol considered a leading cause of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes; however, we know little about the role of lipids in extracellular vesicles (EVs) as regulatory molecules and disease biomarkers. We employed a sensitive lipidomic strategy to characterize lipid species from the plasma EVs of AUD patients to evaluate functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism after alcohol consumption. We analyzed plasma EV lipids from AUD females and males and healthy individuals to highlight lipids with differential abundance and biologically interpreted lipidomics data using LINEX2, which evaluates enzymatic dysregulation using an enrichment algorithm. Our results show, for the first time, that AUD females exhibited more significant substrate-product changes in lysophosphatidylcholine/phosphatidylcholine lipids and phospholipase/acyltransferase activity, which are potentially linked to cancer progression and neuroinflammation. Conversely, AUD males suffer from dysregulated ceramide and sphingomyelin lipids involving sphingomyelinase, sphingomyelin phosphodiesterase, and sphingomyelin synthase activity, which relates to hepatotoxicity. Notably, the analysis of plasma EVs from AUD females and males demonstrates enrichment of lipid ontology terms associated with “negative intrinsic curvature” and “positive intrinsic curvature”, respectively. Our methodological developments support an improved understanding of lipid metabolism and regulatory mechanisms, which contribute to the identification of novel lipid targets and the discovery of sex-specific clinical biomarkers in AUD. Alcohol use disorder (AUD) is one of the most common psychiatric disorders, with the consumption of alcohol considered a leading cause of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes; however, we know little about the role of lipids in extracellular vesicles (EVs) as regulatory molecules and disease biomarkers. We employed a sensitive lipidomic strategy to characterize lipid species from the plasma EVs of AUD patients to evaluate functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism after alcohol consumption. We analyzed plasma EV lipids from AUD females and males and healthy individuals to highlight lipids with differential abundance and biologically interpreted lipidomics data using LINEX2, which evaluates enzymatic dysregulation using an enrichment algorithm. Our results show, for the first time, that AUD females exhibited more significant substrate-product changes in lysophosphatidylcholine/phosphatidylcholine lipids and phospholipase/acyltransferase activity, which are potentially linked to cancer progression and neuroinflammation. Conversely, AUD males suffer from dysregulated ceramide and sphingomyelin l
酒精使用障碍(AUD)是最常见的精神疾病之一,饮酒被认为是全球可预防死亡的主要原因。脂质在细胞膜中发挥着重要的功能作用;然而,我们对细胞外囊泡 (EV) 中脂质作为调节分子和疾病生物标志物的作用知之甚少。我们采用了一种敏感的脂质组学策略来表征 AUD 患者血浆 EVs 中的脂质种类,以评估其功能作用和酶活性网络,从而增进对饮酒后脂质代谢的了解。我们分析了AUD女性、男性和健康人的血浆EV脂质,突出显示了丰度不同的脂质,并利用LINEX2对脂质组学数据进行了生物学解释。我们的研究结果首次表明,AUD 女性在溶血磷脂酰胆碱/磷脂酰胆碱脂质和磷脂酶/酰基转移酶活性方面表现出更显著的底物-产物变化,而这些变化可能与癌症进展和神经炎症有关。相反,澳大拉西亚男性患有神经酰胺和鞘磷脂脂质失调,涉及鞘磷脂酶、鞘磷脂磷酸二酯酶和鞘磷脂合成酶活性,这与肝毒性有关。值得注意的是,对 AUD 女性和男性血浆 EVs 的分析表明,分别与 "负固有曲率 "和 "正固有曲率 "相关的脂质本体术语得到了丰富。我们的研究方法有助于加深对脂质代谢和调控机制的理解,从而有助于鉴定新的脂质靶标和发现 AUD 的性别特异性临床生物标志物。酒精使用障碍(AUD)是最常见的精神疾病之一,饮酒被认为是全球可预防死亡的主要原因。脂质在细胞膜中发挥着重要的功能作用;然而,我们对细胞外囊泡 (EVs) 中脂质作为调节分子和疾病生物标志物的作用知之甚少。我们采用了一种敏感的脂质组学策略来表征 AUD 患者血浆 EVs 中的脂质种类,以评估其功能作用和酶活性网络,从而增进对饮酒后脂质代谢的了解。我们分析了AUD女性、男性和健康人的血浆EV脂质,突出显示了丰度不同的脂质,并利用LINEX2对脂质组学数据进行了生物学解释。我们的研究结果首次表明,AUD 女性在溶血磷脂酰胆碱/磷脂酰胆碱脂质和磷脂酶/酰基转移酶活性方面表现出更显著的底物-产物变化,而这些变化可能与癌症进展和神经炎症有关。相反,澳大拉西亚男性患有神经酰胺和鞘磷脂脂质失调,涉及鞘磷脂酶、鞘磷脂磷酸二酯酶和鞘磷脂合成酶活性,这与肝毒性有关。值得注意的是,对 AUD 女性和男性血浆 EVs 的分析表明,分别与 "负固有曲率 "和 "正固有曲率 "相关的脂质本体术语得到了丰富。我们的研究方法有助于加深对脂质代谢和调控机制的理解,从而有助于鉴定新的脂质靶标和发现 AUD 的性别特异性临床生物标志物。
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引用次数: 0
Dihydrotestosterone induces arterial stiffening in female mice. 二氢睾酮诱导雌性小鼠动脉硬化
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-23 DOI: 10.1186/s13293-024-00586-3
Alec C Horton, Mary M Wilkinson, Isabella Kilanowski-Doroh, Zhejun Dong, Jiao Liu, Benard O Ogola, Bruna Visniauskas, Sarah H Lindsey

Background: Androgens are important sex hormones in both men and women and are supplemented when endogenous levels are low, for gender transitioning, or to increase libido. Androgens also circulate at higher levels in women with polycystic ovarian syndrome, a condition that increases the risk for cardiovascular diseases including hypertension and arterial stiffness. Since our previous work shows an important role for the G protein-coupled estrogen receptor (GPER) in arterial stiffness, we hypothesized that other hormones including androgens may impact arterial stiffness in female mice via downregulation of GPER.

Methods: The impact of the non-aromatizable androgen dihydrotestosterone (DHT), the glucocorticoid dexamethasone, and the progestin medroxyprogesterone acetate (all 100 nM for 24 h) on GPER and ERα expression was assessed in cultured vascular smooth muscle cells using droplet digital PCR (ddPCR). To assess the in vivo impact of the DHT-induced downregulation of GPER, female ovary-intact C57Bl/6 mice at 15-16 weeks of age were treated with silastic capsules containing DHT for 4 weeks, one with a dosage expected to mimic human male DHT levels and another to double the expected human concentration (n = 8-9/group).

Results: In cultured vascular smooth muscle cells, GPER mRNA was decreased by DHT (P = 0.001) but was not impacted by dexamethasone or medroxyprogesterone. In contrast, ERα expression in cultured cells was significantly suppressed by all three hormones (P < 0.0001). In control mice or mice treated with a single or double dose of DHT, a dose-dependent increase in body weight was observed (control 22 ± 2 g, single dose 24 ± 2 g, double dose 26 ± 2 g; P = 0.0002). Intracarotid stiffness measured via pulse wave velocity showed a more than two-fold increase in both DHT-treated groups (control 1.9 ± 0.3 m/s, single dose 4.3 ± 0.8 m/s, double dose 4.8 ± 1.0 m/s). This increase in arterial stiffness occurred independent of changes in blood pressure (P = 0.59). Histological analysis of aortic sections using Masson's trichrome showed a significant decrease in collagen between the control group (24 ± 5%) and the double dose group (17 ± 3%, P = 0.007), despite no changes in aortic wall thickness or smooth muscle content. Lastly, ddPCR showed that in vivo DHT treatment decreased aortic expression of both GPER (control 20 ± 5, single dose 10.5 ± 5.6, double dose 10 ± 4 copies/ng; P = 0.001) and ERα (control 54 ± 2, single dose 24 ± 13, and double dose 23 ± 12 copies/ng; P = 0.003).

Conclusions: These findings indicate that androgen promotes arterial stiffening and cardiovascular damage in female mice and is associated with decreased estrogen receptor expression. These data are important for transgender men, women using testosterone for fitness or reduced libido, as well as patients with polycystic ovarian syndrome.

背景:雄性激素是男性和女性体内重要的性激素,当内源性雄性激素水平较低时、性别转换或提高性欲时都需要补充雄性激素。患有多囊卵巢综合征的女性体内雄激素的循环水平也较高,这种情况会增加患高血压和动脉僵化等心血管疾病的风险。由于我们之前的研究表明 G 蛋白偶联雌激素受体(GPER)在动脉僵化中起着重要作用,因此我们假设包括雄激素在内的其他激素可能会通过下调 GPER 影响雌性小鼠的动脉僵化:方法:在培养的血管平滑肌细胞中,使用液滴数字 PCR(ddPCR)评估了非芳香化雄激素双氢睾酮(DHT)、糖皮质激素地塞米松和孕激素醋酸甲羟孕酮(均为 100 nM,持续 24 小时)对 GPER 和 ERα 表达的影响。为了评估DHT诱导的GPER下调在体内的影响,用含有DHT的硅胶胶囊对15-16周龄的雌性卵巢接触C57Bl/6小鼠进行了为期4周的治疗,其中一个剂量预期模拟人类雄性DHT水平,另一个剂量预期为人类浓度的两倍(n = 8-9/组):在培养的血管平滑肌细胞中,GPER mRNA 受 DHT 影响而降低(P = 0.001),但不受地塞米松或甲羟孕酮的影响。与此相反,培养细胞中的 ERα 表达受到这三种激素的显著抑制(P 结论:DHT、地塞米松和甲羟孕酮均能抑制 ERα 的表达):这些研究结果表明,雄激素会促进雌性小鼠动脉僵化和心血管损伤,并与雌激素受体表达减少有关。这些数据对于变性男性、因健身或性欲减退而使用睾酮的女性以及多囊卵巢综合征患者来说非常重要。
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引用次数: 0
Sex differences for clinical correlates of substantia nigra neuron loss in people with Lewy body pathology 路易体病变患者黑质神经元缺失临床相关性的性别差异
IF 7.9 2区 医学 Q1 Social Sciences Pub Date : 2024-01-19 DOI: 10.1186/s13293-024-00583-6
Ece Bayram, David G. Coughlin, Ravi Rajmohan, Irene Litvan
Lewy body dementia (LBD) phenotype is associated with the presence and degree of Lewy body, Alzheimer’s pathologies, and substantia nigra neuron loss. Nigral neuron loss is associated with parkinsonism in LBD, and females with LBD are less likely than males to have parkinsonism. As sex differences were reported for clinical correlates of Lewy body and Alzheimer’s pathologies, we aimed to investigate whether there are also sex differences for correlates of nigral neuron loss. Data were obtained from the National Alzheimer’s Coordinating Center for females (n = 159) and males (n = 263) with brainstem, limbic, and neocortical Lewy body pathology. Sex differences for the nigral neuron loss’ association with Lewy body pathology staging and core clinical LBD features (cognitive fluctuations, visual hallucinations, rapid eye movement sleep behavior disorder, parkinsonism) during follow-up were analyzed with generalized linear models adjusting for age and Alzheimer’s pathology staging. Whether any of the core clinical features at the time of dementia onset can predict underlying nigral neuron loss for females and males were also analyzed with generalized linear models. Compared to males, females died older and had higher levels of Braak tau staging, but had similar levels of Lewy body pathology staging and nigral neuron loss. Females were less likely than males to have a clinical Lewy body disease diagnosis during follow-up. More advanced Lewy body pathology staging was associated with more nigral neuron loss, more so for males than females. More nigral neuron loss was associated with parkinsonism and clinical LBD diagnosis during follow-up, more so for males than females. Across the subgroup with dementia (40 females, 58 males), core LBD features at first visit with dementia were not associated with nigral neuron loss. Nigral neuron loss’ association with Lewy body pathology staging and core LBD features can differ by sex. Compared to males, females with Lewy body pathology have a higher risk of underdiagnosis. There is a need to elucidate the mechanisms underlying sex differences for pathology and clinicopathological correlations to advance diagnostic and therapeutic efforts in LBD. Lewy body dementia (LBD) is the third most common dementia associated with Lewy body pathology, Alzheimer’s pathology, and substantia nigra loss. It is often less recognized in females compared to males, because the typical symptoms are less evident in females. In this study, we investigated whether substantia nigra neuron loss plays a role in the atypical presentation of LBD in females, contributing to the underdiagnosis compared to males. We analyzed data from 159 females and 263 males with pathological Lewy body disease obtained from the National Alzheimer's Coordinating Center. Females tended to be older at the time of death and had more tau buildup, but similar levels of Lewy body pathology and substantia nigra neuron loss compared to males. When we compared males and
路易体痴呆(LBD)的表型与路易体、阿尔茨海默氏症病变和黑质神经元缺失的存在和程度有关。黑质神经元缺失与路易氏痴呆的帕金森氏症有关,而女性路易氏痴呆患者出现帕金森氏症的可能性低于男性。由于路易体和阿尔茨海默病的临床相关性存在性别差异,我们旨在研究黑质神经元缺失的相关性是否也存在性别差异。我们从国家阿尔茨海默氏症协调中心获得了患有脑干、边缘和新皮质路易体病变的女性(n = 159)和男性(n = 263)的数据。通过调整年龄和阿尔茨海默病分期的广义线性模型,分析了黑质神经元缺失与路易体病理分期和随访期间核心临床特征(认知波动、视幻觉、快速眼动睡眠行为障碍、帕金森病)之间的性别差异。此外,还利用广义线性模型分析了女性和男性痴呆症发病时的核心临床特征是否可以预测潜在的黑质神经元缺失。与男性相比,女性的死亡年龄更大,Braak tau分期水平更高,但路易体病理学分期和黑质神经元缺失水平相似。与男性相比,女性在随访期间被诊断为临床路易体疾病的可能性较低。路易体病理分期越晚,黑质神经元丢失越多,男性比女性更明显。更多的黑质神经元缺失与帕金森症和随访期间的临床路易体疾病诊断有关,男性比女性更为明显。在痴呆症亚组(40 名女性,58 名男性)中,痴呆症患者首次就诊时的枸杞多糖核心特征与黑质神经元缺失无关。黑质神经元缺失与路易体病理学分期和核心枸杞多糖特征的关系可能因性别而异。与男性相比,女性路易体病理患者被漏诊的风险更高。有必要阐明路易体病理学和临床病理学相关性的性别差异机制,以推进路易体痴呆的诊断和治疗工作。路易体痴呆症(LBD)是与路易体病理学、阿尔茨海默氏症病理学和黑质丧失相关的第三大常见痴呆症。与男性相比,女性对这种疾病的认识往往较少,因为女性的典型症状并不明显。在这项研究中,我们探讨了黑质神经元缺失是否是女性枸杞多糖症表现不典型的原因之一,从而导致女性枸杞多糖症的诊断率低于男性。我们分析了从美国国家阿尔茨海默病协调中心(National Alzheimer's Coordinating Center)获得的159名女性和263名男性病理路易体病患者的数据。与男性相比,女性在死亡时往往年龄较大,tau堆积较多,但路易体病理和黑质神经元丢失的程度相似。当我们比较年龄相仿、阿尔茨海默病病理程度相似的男性和女性时,我们发现女性在路易体病理阶段较晚时,黑质神经元丢失较少。在男性中,黑质神经元丢失较多与帕金森氏症和典型的路易体病症状有关,但在女性中则不尽相同。根据痴呆症诊断时的临床特征无法预测黑质神经元缺失的程度。因此,黑质神经元缺失与路易体痴呆症状之间的关系似乎因性别而异。与男性相比,患有潜在路易体疾病的女性更容易被漏诊。我们需要进一步研究,以了解这些性别差异存在的原因,以及如何更好地识别和治疗路易体痴呆症。
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引用次数: 0
Sex-specific differences in intestinal microbiota associated with cardiovascular diseases 与心血管疾病相关的肠道微生物群的性别差异
IF 7.9 2区 医学 Q1 Social Sciences Pub Date : 2024-01-19 DOI: 10.1186/s13293-024-00582-7
Helena Garcia-Fernandez, Antonio P. Arenas-de Larriva, Javier Lopez-Moreno, Francisco M. Gutierrez-Mariscal, Juan L. Romero-Cabrera, Helena Molina-Abril, Jose D. Torres-Peña, Diego Rodriguez-Cano, Maria M. Malagon, Jose M. Ordovas, Javier Delgado-Lista, Pablo Perez-Martinez, Jose Lopez-Miranda, Antonio Camargo
Cardiovascular diseases (CVD), including coronary heart disease (CHD), display a higher prevalence in men than women. This study aims to evaluate the variations in the intestinal microbiota between men and women afflicted with CHD and delineate these against a non-CVD control group for each sex. Our research was conducted in the framework of the CORDIOPREV study, a clinical trial which involved 837 men and 165 women with CHD. We contrasted our findings with a reference group of 375 individuals (270 men, 105 women) without CVD. The intestinal microbiota was examined through 16S metagenomics on the Illumina MiSeq platform and the data processed with Quiime2 software. Our results showed a sex-specific variation (beta diversity) in the intestinal microbiota, while alpha-biodiversity remained consistent across both sexes. Linear discriminant analysis effect size (LEfSe) analysis revealed sex-centric alterations in the intestinal microbiota linked to CVD. Moreover, using random forest (RF) methodology, we identified seven bacterial taxa—g_UBA1819 (Ruminococcaceae), g_Bilophila, g_Subdoligranulum, g_Phascolarctobacterium, f_Barnesiellaceae, g_Ruminococcus, and an unknown genus from the Ruminococcaceae family (Ruminococcaceae incertae sedis)—as key discriminators between men and women diagnosed with CHD. The same taxa also emerged as critical discriminators between CHD-afflicted and non-CVD individuals, when analyzed separately by sex. Our findings suggest a sex-specific dysbiosis in the intestinal microbiota linked to CHD, potentially contributing to the sex disparity observed in CVD incidence. Trial registration Clinical Trials.gov.Identifier NCT00924937. The frequency with which cardiovascular diseases occur differs in men and women as it appears with greater frequency in men. Moreover, it has been known for years that the community of bacteria living in our intestine, also known as the gut microbiota, influences the development of these diseases. Indeed, nowadays it known the influence of the intestinal microbiota in the development of atherosclerosis, the pathological process which is responsible for the three main causes of cardiovascular diseases: coronary heart disease, cerebrovascular disease and peripheral arterial disease. This study shows the differences in the community of bacteria living in the gut of men and those living in the gut of women, so that these differences could explain, at least in part, the differences in the frequency with which cardiovascular diseases appear between men and women. Our results suggest that the dysbiosis of the intestinal microbiota associated with CHD seems to be partially sex-specific, which may influence the sexual dimorphism in its incidence. Moreover, the identification of the mechanisms responsible for sexual dimorphism in the incidence of metabolic and cardiovascular disease is of particular importance when developing effective strategies and therapies aimed at reducing their incidence and recurrence. I
心血管疾病(CVD),包括冠心病(CHD),在男性中的发病率高于女性。本研究旨在评估患有冠心病的男性和女性之间肠道微生物群的变化,并将这些变化与非冠心病对照组进行对比。我们的研究是在 CORDIOPREV 研究的框架内进行的,该临床试验涉及 837 名男性和 165 名女性心脏病患者。我们将研究结果与 375 名无心血管疾病的参照组(男性 270 人,女性 105 人)进行了对比。我们在 Illumina MiSeq 平台上通过 16S 元基因组学对肠道微生物群进行了检测,并使用 Quiime2 软件对数据进行了处理。我们的研究结果表明,肠道微生物群存在性别差异(β多样性),而α-生物多样性在两性中保持一致。线性判别分析效应大小(LEfSe)分析揭示了与心血管疾病相关的肠道微生物群以性别为中心的改变。此外,利用随机森林(RF)方法,我们发现了七个细菌类群-g_UBA1819(Ruminococcaceae)、g_Bilophila、g_Subdoligranulum、g_Phascolarctobacterium、f_Barnesiellaceae、g_Ruminococcus 和 Ruminococcaceae 家族中的一个未知属(Ruminococcaceae incertae sedis)-是诊断出患有心血管疾病的男性和女性之间的关键判别因素。按性别单独分析时,同样的分类群也是区分冠心病患者和非冠心病患者的关键因素。我们的研究结果表明,肠道微生物群存在与冠心病相关的性别特异性菌群失调,这可能是导致心血管疾病发病率性别差异的原因之一。试验注册 Clinical Trials.gov.Identifier NCT00924937.心血管疾病在男性和女性中的发病率不同,因为男性的发病率更高。此外,人们多年来一直知道,生活在我们肠道中的细菌群落(也称为肠道微生物群)会影响这些疾病的发生。事实上,如今人们已经知道肠道微生物群对动脉粥样硬化发展的影响,而动脉粥样硬化是导致心血管疾病的三大主要原因:冠心病、脑血管疾病和外周动脉疾病的病理过程。这项研究表明,生活在男性肠道中的细菌群落与生活在女性肠道中的细菌群落存在差异,因此这些差异至少可以部分解释男女之间心血管疾病发生频率的差异。我们的研究结果表明,与冠心病相关的肠道微生物群失调似乎具有部分性别特异性,这可能会影响冠心病发病率的性别二态性。此外,在制定旨在减少代谢性疾病和心血管疾病的发病率和复发率的有效策略和疗法时,确定导致代谢性疾病和心血管疾病发病率性别双态性的机制尤为重要。事实上,用于治疗肠道微生物群失调的策略和疗法应具有性别特异性。
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引用次数: 0
Sex-dependent circadian alterations of both central and peripheral clock genes expression and gut-microbiota composition during activity-based anorexia in mice. 小鼠活动性厌食症期间中枢和外周时钟基因表达及肠道微生物群组成的昼夜节律变化与性别有关。
IF 7.9 2区 医学 Q1 Social Sciences Pub Date : 2024-01-12 DOI: 10.1186/s13293-023-00576-x
Colin Salaün, Marine Courvalet, Léna Rousseau, Kévin Cailleux, Jonathan Breton, Christine Bôle-Feysot, Charlène Guérin, Marion Huré, Alexis Goichon, Jean-Claude do Rego, Pierre Déchelotte, David Ribet, Najate Achamrah, Moïse Coëffier

Rationale: Patients with anorexia nervosa (AN) often present sleep disorders and circadian hormonal dysregulation. The role of the microbiota-gut-brain axis in the regulation of feeding behavior has emerged during the last decades but its relationships with the circadian rhythm remains poorly documented. Thus, we aimed to characterize the circadian clock genes expression in peripheral and central tissues in the activity-based anorexia mouse model (ABA), as well as the dynamics of the gut-microbiota composition.

Methods: From day 1 to day 17, male and female C57Bl/6 mice were submitted or not to the ABA protocol (ABA and control (CT) groups), which combines a progressive limited access to food and a free access to a running wheel. At day 17, fasted CT and ABA mice were euthanized after either resting (EoR) or activity (EoA) phase (n = 10-12 per group). Circadian clock genes expression was assessed by RT-qPCR on peripheral (liver, colon and ileum) and central (hypothalamic suprachiasmatic nucleus or SCN) tissues. Cecal bacterial taxa abundances were evaluated by qPCR. Data were compared by two-way ANOVA followed by post-tests.

Results: ABA mice exhibited a lower food intake, a body weight loss and an increase of diurnal physical activity that differ according with the sex. Interestingly, in the SCN, only ABA female mice exhibited altered circadian clock genes expression (Bmal1, Per1, Per2, Cry1, Cry2). In the intestinal tract, modification of clock genes expression was also more marked in females compared to males. For instance, in the ileum, female mice showed alteration of Bmal1, Clock, Per1, Per2, Cry1, Cry2 and Rev-erbα mRNA levels, while only Per2 and Cry1 mRNAs were affected by ABA model in males. By contrast, in the liver, clock genes expression was more markedly affected in males compared to females in response to ABA. Finally, circadian variations of gut-bacteria abundances were observed in both male and female mice and sex-dependent alteration were observed in response to the ABA model.

Conclusions: This study shows that alteration of circadian clock genes expression at both peripheral and central levels occurs in response to the ABA model. In addition, our data underline that circadian variations of the gut-microbiota composition are sex-dependent.

理论依据:神经性厌食症(AN)患者通常会出现睡眠障碍和昼夜节律激素失调。微生物群-肠-脑轴在调节进食行为中的作用在过去几十年中已经出现,但其与昼夜节律的关系仍鲜有记载。因此,我们旨在研究基于活动的厌食症小鼠模型(ABA)的外周和中枢组织中昼夜节律钟基因表达的特征,以及肠道微生物群组成的动态变化:从第1天到第17天,雌雄C57Bl/6小鼠均接受或不接受ABA方案(ABA组和对照(CT)组)。第17天,禁食的CT组和ABA组小鼠在休息(EoR)或活动(EoA)阶段后被安乐死(每组n = 10-12)。外周(肝脏、结肠和回肠)和中枢(下丘脑丘上核或 SCN)组织的昼夜节律表基因表达通过 RT-qPCR 进行评估。通过 qPCR 评估了盲肠细菌类群的丰度。数据通过双向方差分析进行比较,然后进行后检验:结果:ABA 小鼠的食物摄入量降低、体重减轻、昼夜体力活动增加,这些表现因性别而异。有趣的是,只有雌性 ABA 小鼠的昼夜节律时钟基因(Bmal1、Per1、Per2、Cry1、Cry2)表达发生了改变。在肠道中,雌性小鼠与雄性小鼠相比,时钟基因表达的改变也更为明显。例如,在回肠中,雌性小鼠的Bmal1、Clock、Per1、Per2、Cry1、Cry2和Rev-erbα mRNA水平发生了改变,而雄性小鼠只有Per2和Cry1 mRNA受到ABA模型的影响。相比之下,在肝脏中,雄性的时钟基因表达受 ABA 的影响比雌性更明显。最后,在雄性和雌性小鼠体内都观察到了肠道细菌丰度的昼夜节律变化,并观察到了对 ABA 模型反应的性别依赖性改变:结论:这项研究表明,昼夜节律时钟基因在外周和中枢水平的表达都会随着 ABA 模型的变化而改变。此外,我们的数据还强调了肠道微生物群组成的昼夜节律变化是性别依赖性的。
{"title":"Sex-dependent circadian alterations of both central and peripheral clock genes expression and gut-microbiota composition during activity-based anorexia in mice.","authors":"Colin Salaün, Marine Courvalet, Léna Rousseau, Kévin Cailleux, Jonathan Breton, Christine Bôle-Feysot, Charlène Guérin, Marion Huré, Alexis Goichon, Jean-Claude do Rego, Pierre Déchelotte, David Ribet, Najate Achamrah, Moïse Coëffier","doi":"10.1186/s13293-023-00576-x","DOIUrl":"10.1186/s13293-023-00576-x","url":null,"abstract":"<p><strong>Rationale: </strong>Patients with anorexia nervosa (AN) often present sleep disorders and circadian hormonal dysregulation. The role of the microbiota-gut-brain axis in the regulation of feeding behavior has emerged during the last decades but its relationships with the circadian rhythm remains poorly documented. Thus, we aimed to characterize the circadian clock genes expression in peripheral and central tissues in the activity-based anorexia mouse model (ABA), as well as the dynamics of the gut-microbiota composition.</p><p><strong>Methods: </strong>From day 1 to day 17, male and female C57Bl/6 mice were submitted or not to the ABA protocol (ABA and control (CT) groups), which combines a progressive limited access to food and a free access to a running wheel. At day 17, fasted CT and ABA mice were euthanized after either resting (EoR) or activity (EoA) phase (n = 10-12 per group). Circadian clock genes expression was assessed by RT-qPCR on peripheral (liver, colon and ileum) and central (hypothalamic suprachiasmatic nucleus or SCN) tissues. Cecal bacterial taxa abundances were evaluated by qPCR. Data were compared by two-way ANOVA followed by post-tests.</p><p><strong>Results: </strong>ABA mice exhibited a lower food intake, a body weight loss and an increase of diurnal physical activity that differ according with the sex. Interestingly, in the SCN, only ABA female mice exhibited altered circadian clock genes expression (Bmal1, Per1, Per2, Cry1, Cry2). In the intestinal tract, modification of clock genes expression was also more marked in females compared to males. For instance, in the ileum, female mice showed alteration of Bmal1, Clock, Per1, Per2, Cry1, Cry2 and Rev-erbα mRNA levels, while only Per2 and Cry1 mRNAs were affected by ABA model in males. By contrast, in the liver, clock genes expression was more markedly affected in males compared to females in response to ABA. Finally, circadian variations of gut-bacteria abundances were observed in both male and female mice and sex-dependent alteration were observed in response to the ABA model.</p><p><strong>Conclusions: </strong>This study shows that alteration of circadian clock genes expression at both peripheral and central levels occurs in response to the ABA model. In addition, our data underline that circadian variations of the gut-microbiota composition are sex-dependent.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10785476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139431841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Sex differences in a mouse model of diet-induced obesity: the role of the gut microbiome 饮食诱发肥胖小鼠模型的性别差异:肠道微生物组的作用
IF 7.9 2区 医学 Q1 Social Sciences Pub Date : 2024-01-10 DOI: 10.1186/s13293-023-00580-1
Saluda Stapleton, Grace Welch, Lindsay DiBerardo, Linnea R Freeman
Recent decades have seen an exponential rise in global obesity prevalence, with rates nearly doubling in a span of 40 years. A comprehensive knowledge base regarding the systemic effects of obesity is required to create new preventative and therapeutic agents effective at combating the current obesity epidemic. Previous studies of diet-induced obesity utilizing mouse models have demonstrated a difference in bodyweight gain by sex. In such studies, female mice gained significantly less weight than male mice when given the same high fat (HF) diet, indicating a resistance to diet-induced obesity. Research has also shown sex differences in gut microbiome composition between males and females, indicated to be in part a result of sex hormones. Understanding metabolic differences between sexes could assist in the development of new measures for obesity prevention and treatment. This study aimed to characterize sex differences in weight gain, plasma lipid profiles, fecal microbiota composition, and fecal short chain fatty acid levels. We hypothesized a role for the gut microbiome in these sex differences that would be normalized following microbiome depletion. A mouse model was used to study these effects. Mice were divided into treatment groups by sex, diet, and presence/absence of an antibiotic cocktail to deplete genera in the gut microbiome. We hypothesized that sex differences would be present both in bodyweight gain and systemic measures of obesity, including hormone and circulating free fatty acid levels. We determined statistically significant differences for sex and/or treatment for the outcome measures. We confirm previous findings in which male mice gained significantly more weight than female mice fed the same high fat diet. However, sex differences persisted following antibiotic administration for microbiome depletion. We conclude that sex differences in the gut microbiome may contribute to sex differences in obesity, but they do not explain all of the differences.
近几十年来,全球肥胖症发病率呈指数级增长,在 40 年间几乎翻了一番。我们需要全面了解肥胖症的系统性影响,以便开发新的预防和治疗药物,有效对抗当前肥胖症的流行。以前利用小鼠模型进行的饮食诱发肥胖症研究表明,体重增加因性别而异。在这些研究中,雌性小鼠在摄入相同的高脂肪(HF)饮食时,体重增加明显少于雄性小鼠,这表明雌性小鼠对饮食诱发的肥胖具有抵抗力。研究还显示,雄性和雌性肠道微生物组的组成存在性别差异,这在一定程度上是性激素的结果。了解性别之间的代谢差异有助于开发预防和治疗肥胖症的新措施。本研究旨在描述体重增加、血浆脂质概况、粪便微生物群组成和粪便短链脂肪酸水平的性别差异。我们假设肠道微生物群在这些性别差异中的作用,而这些差异会在微生物群耗竭后恢复正常。我们使用小鼠模型来研究这些影响。小鼠按性别、饮食和是否使用抗生素鸡尾酒来消耗肠道微生物群中的菌属被分为不同的处理组。我们假设在体重增加和肥胖的系统测量(包括激素和循环游离脂肪酸水平)方面都会出现性别差异。我们确定,在结果测量方面,性别和/或治疗方法的差异具有统计学意义。我们证实了之前的研究结果,即雄性小鼠的体重增加明显多于以相同高脂肪饮食喂养的雌性小鼠。然而,在使用抗生素消耗微生物组后,性别差异依然存在。我们的结论是,肠道微生物组的性别差异可能会导致肥胖的性别差异,但并不能解释所有的差异。
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引用次数: 0
Sex and gender correlates of sexually polymorphic cognition 性多态认知的性和性别相关性
IF 7.9 2区 医学 Q1 Social Sciences Pub Date : 2024-01-08 DOI: 10.1186/s13293-023-00579-8
Louis Cartier, Mina Guérin, Fanny Saulnier, Ioana Cotocea, Amine Mohammedi, Fadila Moussaoui, Sarah Kheloui, Robert-Paul Juster
Sexually polymorphic cognition (SPC) results from the interaction between biological (birth-assigned sex (BAS), sex hormones) and socio-cultural (gender identity, gender roles, sexual orientation) factors. The literature remains quite mixed regarding the magnitude of the effects of these variables. This project used a battery of classic cognitive tests designed to assess the influence of sex hormones on cognitive performance. At the same time, we aimed to assess the inter-related and respective effects that BAS, sex hormones, and gender-related factors have on SPC. We recruited 222 adults who completed eight cognitive tasks that assessed a variety of cognitive domains during a 150-min session. Subgroups were separated based on gender identity and sexual orientation and recruited as follows: cisgender heterosexual men (n = 46), cisgender non-heterosexual men (n = 36), cisgender heterosexual women (n = 36), cisgender non-heterosexual women (n = 38), gender diverse (n = 66). Saliva samples were collected before, during, and after the test to assess testosterone, estradiol, progesterone, cortisol, and dehydroepiandrosterone. Psychosocial variables were derived from self-report questionnaires. Cognitive performance reflects sex and gender differences that are partially consistent with the literature. Interestingly, biological factors seem to better explain differences in male-typed cognitive tasks (i.e., spatial), while psychosocial factors seem to better explain differences in female-typed cognitive tasks (i.e., verbal). Our results establish a better comprehension of SPC over and above the effects of BAS as a binary variable. We highlight the importance of treating sex as a biological factor and gender as a socio-cultural factor together since they collectively influence SPC. Many studies show sex differences in cognitive abilities. In general, women outperform men in verbal tasks and fine motor skills, while men outperform women in spatial orientation and mental rotation tasks. These differences underlie research on sexually polymorphic cognition, a concept influenced by sex hormones (estradiol, progesterone, and testosterone) as well as birth-assigned sex. In addition to these biological factors, socio-cultural gender factors such as gender identity (the gender we feel and embody), gender roles (masculine and feminine expressions based on stereotypes), as well as sexual orientation are all known to influence cognition as well. We provide a broader understanding by accounting for both sex and gender factors. Our team recruited 222 adults separated into 5 sub-groups based on birth-assigned sex, gender identity, and sexual orientation. Each participant completed eight sexually polymorphic cognitive tasks. In this 150-min experimental protocol, saliva samples were collected before, during, and after the test to assess testosterone, estradiol, progesterone, cortisol, and dehydroepiandrosterone. Psychosocial variables were derived from self-report quest
性别多态性认知(SPC)是生物因素(出生性别(BAS)、性激素)和社会文化因素(性别认同、性别角色、性取向)相互作用的结果。关于这些变量的影响程度,目前的文献仍是众说纷纭。本项目采用了一系列经典认知测试,旨在评估性激素对认知能力的影响。同时,我们还旨在评估 BAS、性激素和性别相关因素对 SPC 的相互关联和各自影响。我们招募了 222 名成年人,他们在 150 分钟的时间内完成了八项认知任务,这些任务评估了各种认知领域。我们根据性别认同和性取向划分了以下分组:顺性别异性恋男性(n = 46)、顺性别非异性恋男性(n = 36)、顺性别异性恋女性(n = 36)、顺性别非异性恋女性(n = 38)、性别多元化(n = 66)。在测试前、测试中和测试后收集唾液样本,以评估睾酮、雌二醇、孕酮、皮质醇和脱氢表雄酮。社会心理变量来自自我报告问卷。认知表现反映出的性和性别差异部分与文献报道一致。有趣的是,生物因素似乎更能解释男性类型认知任务(即空间)的差异,而社会心理因素似乎更能解释女性类型认知任务(即语言)的差异。我们的研究结果证明,除了作为二元变量的 BAS 的影响之外,我们还能更好地理解 SPC。我们强调了将性作为生物因素和性别作为社会文化因素一并处理的重要性,因为它们共同影响着 SPC。许多研究表明,认知能力存在性别差异。一般来说,女性在语言任务和精细动作技能方面优于男性,而男性在空间定向和心理旋转任务方面优于女性。性激素(雌二醇、孕酮和睾酮)以及出生时指定的性别对这一概念产生了影响。除了这些生物因素外,性别认同(我们感觉和体现的性别)、性别角色(基于刻板印象的男性和女性表达方式)以及性取向等社会文化性别因素也会影响认知。我们通过对性和性别因素的考虑,提供了一种更广泛的理解。我们的团队招募了 222 名成年人,根据出生时指定的性别、性别认同和性取向分成 5 个子组。每位参与者都完成了八项性别多态认知任务。在这个 150 分钟的实验方案中,测试前、测试中和测试后都会收集唾液样本,以评估睾酮、雌二醇、孕酮、皮质醇和脱氢表雄酮。社会心理变量来自自我报告问卷。结果显示,生理性别因素能更好地解释空间认知,而社会文化性别因素能更好地解释语言认知。综上所述,我们的研究结果表明,在研究认知中的性别差异时,分别考虑基于性和基于性别的因素非常重要。
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引用次数: 0
Sex-dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes. 亚致死铜浓度对星形胶质细胞中胆固醇合成的性别依赖性影响及其与神经元膜中胆固醇和淀粉样前体蛋白水平变化的可能联系
IF 7.9 2区 医学 Q1 Social Sciences Pub Date : 2024-01-08 DOI: 10.1186/s13293-023-00578-9
Marlene Zubillaga, Julia Tau, Diana Rosa, M José Bellini, Nathalie Arnal

Background: Cholesterol (Cho) is an essential lipophilic molecule in cells; however, both its decrease and its increase may favor the development of neurological diseases such as Alzheimer's disease (AD). Although copper (Cu) is an essential trace metal for cells, the increased plasma concentration of its free form has been linked with AD development and severity. AD affects aged people, but its prevalence and severity are higher in women than in men. We have previously shown that Cu promotes Cho de novo synthesis in immature neurons as well as increased Cho in membrane rafts and Aβ levels in culture medium, but there are no results yet regarding sex differences in the effects of sublethal Cu exposure on Cho de novo synthesis.

Methods: We examined the potential sex-specific impact of sublethal Cu concentrations on de novo Cho synthesis in primary cultures of male and female astrocytes. We also explored whether this had any correlation with variations in Cho and APP levels within neuronal membrane rafts.

Results: Flow cytometry analysis demonstrated that Cu treatment leads to a greater increase in ROS levels in female astrocytes than in males. Furthermore, through RT-PCR analysis, we observed an upregulation of SREBP-2 and HMGCR. Consistently, we observed an increase in de novo Cho synthesis. Finally, western blot analysis indicated that the levels of ABCA1 increase after Cu treatment, accompanied by a higher release of radiolabeled Cho and an elevation in Cho and APP levels in neuronal membrane rafts. Importantly, all these results were significantly more pronounced in female astrocytes than in males.

Conclusions: Our findings confirm that Cu stimulates Cho synthesis in astrocytes, both in a ROS-dependent and -independent manner. Moreover, female astrocytes displayed elevated levels of HMGCR, and de novo Cho synthesis compared to males following TBH and Cu treatments. This corresponds with higher levels of Cho released into the culture medium and a more significant Cho and APP rise within neuronal rafts. We consider that the increased risk of AD in females partly arises from sex-specific responses to metals and/or exogenous substances, impacting key enzyme regulation in various biochemical pathways, including HMGCR.

背景:胆固醇(Cholesterol,Cho)是细胞中不可或缺的亲脂分子;然而,胆固醇的减少和增加都可能有利于阿尔茨海默病(Alzheimer's disease,AD)等神经系统疾病的发展。虽然铜(Cu)是细胞不可或缺的微量金属,但其游离形式的血浆浓度增加与阿尔茨海默病的发展和严重程度有关。老年痴呆症影响着老年人,但女性的发病率和严重程度均高于男性。我们曾研究发现,Cu能促进未成熟神经元中Cho的从头合成以及膜筏中Cho的增加和培养基中Aβ水平的提高,但关于亚致死性Cu暴露对Cho从头合成影响的性别差异还没有结果:我们研究了亚致死性 Cu 浓度对男性和女性星形胶质细胞原代培养液中 Cho 从头合成的潜在性别特异性影响。我们还探讨了这是否与神经元膜筏中 Cho 和 APP 水平的变化有关:流式细胞术分析表明,Cu 处理导致雌性星形胶质细胞的 ROS 水平比雄性更高。此外,通过 RT-PCR 分析,我们观察到 SREBP-2 和 HMGCR 的上调。同样,我们也观察到 Cho 的合成增加。最后,Western 印迹分析表明,铜处理后 ABCA1 的水平升高,同时放射性标记的 Cho 释放量增加,神经元膜筏中 Cho 和 APP 的水平升高。重要的是,所有这些结果在雌性星形胶质细胞中明显比在雄性星形胶质细胞中更明显:我们的研究结果证实,Cu 能以 ROS 依赖性和非依赖性方式刺激星形胶质细胞中 Cho 的合成。此外,与男性相比,女性星形胶质细胞在接受 TBH 和 Cu 处理后,其 HMGCR 水平和新 Cho 合成水平均有所提高。这与更高水平的 Cho 释放到培养基中以及神经元筏内更显著的 Cho 和 APP 上升相吻合。我们认为,女性罹患注意力缺失症的风险增加,部分原因是女性对金属和/或外源物质的特异性反应影响了各种生化途径中的关键酶调控,包括HMGCR。
{"title":"Sex-dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes.","authors":"Marlene Zubillaga, Julia Tau, Diana Rosa, M José Bellini, Nathalie Arnal","doi":"10.1186/s13293-023-00578-9","DOIUrl":"10.1186/s13293-023-00578-9","url":null,"abstract":"<p><strong>Background: </strong>Cholesterol (Cho) is an essential lipophilic molecule in cells; however, both its decrease and its increase may favor the development of neurological diseases such as Alzheimer's disease (AD). Although copper (Cu) is an essential trace metal for cells, the increased plasma concentration of its free form has been linked with AD development and severity. AD affects aged people, but its prevalence and severity are higher in women than in men. We have previously shown that Cu promotes Cho de novo synthesis in immature neurons as well as increased Cho in membrane rafts and Aβ levels in culture medium, but there are no results yet regarding sex differences in the effects of sublethal Cu exposure on Cho de novo synthesis.</p><p><strong>Methods: </strong>We examined the potential sex-specific impact of sublethal Cu concentrations on de novo Cho synthesis in primary cultures of male and female astrocytes. We also explored whether this had any correlation with variations in Cho and APP levels within neuronal membrane rafts.</p><p><strong>Results: </strong>Flow cytometry analysis demonstrated that Cu treatment leads to a greater increase in ROS levels in female astrocytes than in males. Furthermore, through RT-PCR analysis, we observed an upregulation of SREBP-2 and HMGCR. Consistently, we observed an increase in de novo Cho synthesis. Finally, western blot analysis indicated that the levels of ABCA1 increase after Cu treatment, accompanied by a higher release of radiolabeled Cho and an elevation in Cho and APP levels in neuronal membrane rafts. Importantly, all these results were significantly more pronounced in female astrocytes than in males.</p><p><strong>Conclusions: </strong>Our findings confirm that Cu stimulates Cho synthesis in astrocytes, both in a ROS-dependent and -independent manner. Moreover, female astrocytes displayed elevated levels of HMGCR, and de novo Cho synthesis compared to males following TBH and Cu treatments. This corresponds with higher levels of Cho released into the culture medium and a more significant Cho and APP rise within neuronal rafts. We consider that the increased risk of AD in females partly arises from sex-specific responses to metals and/or exogenous substances, impacting key enzyme regulation in various biochemical pathways, including HMGCR.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10775608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139401649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Sex-based disparities in DNA methylation and gene expression in late-gestation mouse placentas. 妊娠晚期小鼠胎盘中 DNA 甲基化和基因表达的性别差异
IF 7.9 2区 医学 Q1 Social Sciences Pub Date : 2024-01-06 DOI: 10.1186/s13293-023-00577-w
Lisa-Marie Legault, Mélanie Breton-Larrivée, Alexandra Langford-Avelar, Anthony Lemieux, Serge McGraw

Background: The placenta is vital for fetal development and its contributions to various developmental issues, such as pregnancy complications, fetal growth restriction, and maternal exposure, have been extensively studied in mice. The placenta forms mainly from fetal tissue and therefore has the same biological sex as the fetus it supports. Extensive research has delved into the placenta's involvement in pregnancy complications and future offspring development, with a notable emphasis on exploring sex-specific disparities. However, despite these investigations, sex-based disparities in epigenetic (e.g., DNA methylation) and transcriptomic features of the late-gestation mouse placenta remain largely unknown.

Methods: We collected male and female mouse placentas at late gestation (E18.5, n = 3/sex) and performed next-generation sequencing to identify genome-wide sex differences in transcription and DNA methylation.

Results: Our comparison between male and female revealed 358 differentially expressed genes (DEGs) on autosomes, which were associated with signaling pathways involved in transmembrane transport and the responses to viruses and external stimuli. X chromosome DEGs (n = 39) were associated with different pathways, including those regulating chromatin modification and small GTPase-mediated signal transduction. Differentially methylated regions (DMRs) were more common on the X chromosomes (n = 3756) than on autosomes (n = 1705). Interestingly, while most X chromosome DMRs had higher DNA methylation levels in female placentas and tended to be included in CpG dinucleotide-rich regions, 73% of autosomal DMRs had higher methylation levels in male placentas and were distant from CpG-rich regions. Several DEGs were correlated with DMRs. A subset of the DMRs present in late-stage placentas were already established in mid-gestation (E10.5) placentas (n = 348 DMRs on X chromosome and 19 DMRs on autosomes), while others were acquired later in placental development.

Conclusion: Our study provides comprehensive lists of DEGs and DMRs between male and female that collectively cause profound differences in the DNA methylation and gene expression profiles of late-gestation mouse placentas. Our results demonstrate the importance of incorporating sex-specific analyses into epigenetic and transcription studies to enhance the accuracy and comprehensiveness of their conclusions and help address the significant knowledge gap regarding how sex differences influence placental function.

背景:胎盘对胎儿的发育至关重要,胎盘对各种发育问题(如妊娠并发症、胎儿生长受限和母体暴露)的影响已在小鼠中得到广泛研究。胎盘主要由胎儿组织形成,因此与其所支持的胎儿具有相同的生物学性别。研究人员对胎盘参与妊娠并发症和后代发育的情况进行了广泛的研究,重点是探索性别差异。然而,尽管进行了这些研究,小鼠妊娠晚期胎盘在表观遗传学(如 DNA 甲基化)和转录组学特征方面的性别差异在很大程度上仍然是未知的:方法:我们收集了妊娠晚期(E18.5,n = 3/性别)的雄性和雌性小鼠胎盘,并进行了新一代测序,以确定转录和DNA甲基化的全基因组性别差异:结果:我们对雌雄胎儿进行了比较,发现常染色体上有358个差异表达基因(DEGs),这些基因与信号通路有关,涉及跨膜运输以及对病毒和外部刺激的反应。X 染色体 DEGs(n = 39)与不同的途径有关,包括调节染色质修饰和小 GTP 酶介导的信号转导的途径。与常染色体(n = 1705)相比,X 染色体上的差异甲基化区域(DMRs)更常见(n = 3756)。有趣的是,虽然大多数 X 染色体 DMR 在女性胎盘中的 DNA 甲基化水平较高,而且往往包含在 CpG 二核苷酸丰富的区域中,但 73% 的常染色体 DMR 在男性胎盘中的甲基化水平较高,而且远离 CpG 丰富的区域。一些 DEGs 与 DMRs 相关。出现在晚期胎盘中的 DMRs 子集已在妊娠中期(E10.5)胎盘中建立(X 染色体上有 348 个 DMRs,常染色体上有 19 个 DMRs),而其他 DMRs 则是在胎盘发育后期获得的:我们的研究提供了雌雄胎盘间 DEGs 和 DMRs 的综合列表,这些 DEGs 和 DMRs 共同导致了晚期妊娠小鼠胎盘 DNA 甲基化和基因表达谱的深刻差异。我们的研究结果表明了将性别特异性分析纳入表观遗传学和转录研究的重要性,以提高其结论的准确性和全面性,并帮助解决有关性别差异如何影响胎盘功能的重大知识空白。
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引用次数: 0
TrkB-mediated sustained neuroprotection is sex-specific and (text{ER}alpha)-dependent in adult mice following neonatal hypoxia ischemia 在新生儿缺氧缺血后的成年小鼠中,TrkB介导的持续神经保护具有性别特异性和(text{ER}alpha)依赖性
IF 7.9 2区 医学 Q1 Social Sciences Pub Date : 2024-01-04 DOI: 10.1186/s13293-023-00573-0
Vishal Chanana, Margaret Hackett, Nazli Deveci, Nur Aycan, Burak Ozaydin, Nur Sena Cagatay, Damla Hanalioglu, Douglas B. Kintner, Karson Corcoran, Sefer Yapici, Furkan Camci, Jens Eickhoff, Karyn M. Frick, Peter Ferrazzano, Jon E. Levine, Pelin Cengiz
Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of life-long neurological morbidities that result in learning and memory impairments. Evidence suggests that male neonates are more susceptible to the detrimental effects of HI, yet the mechanisms mediating these sex-specific responses to neural injury in neonates remain poorly understood. We previously tested the effects of treatment with a small molecule agonist of the tyrosine kinase B receptor (TrkB), 7,8-dihydroxyflavone (DHF) following neonatal HI and determined that females, but not males exhibit increased phosphorylation of TrkB and reduced apoptosis in their hippocampi. Moreover, these female-specific effects of the TrkB agonist were found to be dependent upon the expression of $$text{ER}alpha$$ . These findings demonstrated that TrkB activation in the presence of $$text{ER}alpha$$ comprises one pathway by which neuroprotection may be conferred in a female-specific manner. The goal of this study was to determine the role of $$text{ER}alpha$$ -dependent TrkB-mediated neuroprotection in memory and anxiety in young adult mice exposed to HI during the neonatal period. In this study, we used a unilateral hypoxic ischemic (HI) mouse model. $$text{ER}alpha$$ +/+ or $$text{ER}alpha$$ −/− mice were subjected to HI on postnatal day (P) 9 and mice were treated with either vehicle control or the TrkB agonist, DHF, for 7 days following HI. When mice reached young adulthood, we used the novel object recognition, novel object location and open field tests to assess long-term memory and anxiety-like behavior. The brains were then assessed for tissue damage using immunohistochemistry. Neonatal DHF treatment prevented HI-induced decrements in recognition and location memory in adulthood in females, but not in males. This protective effect was absent in female mice lacking $$text{ER}alpha$$ . The female-specific improved recognition and location memory outcomes in adulthood conferred by DHF therapy after neonatal HI tended to be or were $$text{ER}alpha$$ -dependent, respectively. Interestingly, DHF triggered anxiety-like behavior in both sexes only in the mice that lacked $$text{ER}alpha$$ . When we assessed the severity of injury, we found that DHF therapy did not decrease the percent tissue loss in proportion to functional recovery. We additionally observed that the presence of $$text{ER}alpha$$ significantly reduced overall HI-associated mortality in both sexes. These observations provide evidence for a therapeutic role for DHF in which TrkB-mediated sustained recovery of recognition and location memories in females are $$text{ER}alpha$$ -associated and dependent, respectively. However, the beneficial effects of DHF therapy did not include reduction of gross tissue loss but may be derived from the enhanced functioning of residual tissues in a cell-specific manner. Periods of low oxygen delivery and blood flow to the brains of newborns are known to cause life-long impairments
与新生儿缺氧缺血(HI)相关的脑损伤是导致学习和记忆障碍的终生神经系统疾病的主要原因之一。有证据表明,男性新生儿更容易受到 HI 的有害影响,但人们对新生儿神经损伤的这些性别特异性反应的介导机制仍然知之甚少。我们之前测试了新生儿HI后使用酪氨酸激酶B受体(TrkB)的小分子激动剂--7,8-二羟基黄酮(DHF)治疗的效果,结果发现,雌性而非雄性海马中的TrkB磷酸化增加,细胞凋亡减少。此外,还发现TrkB激动剂对雌性的特异性作用依赖于$text{ER}alpha$$的表达。这些研究结果表明,在$text{ER}alpha$存在的情况下,TrkB的激活是以女性特异性方式提供神经保护的一种途径。本研究的目的是确定$text{ER}alpha$依赖的TrkB介导的神经保护在新生儿期暴露于HI的年轻成年小鼠的记忆和焦虑中的作用。在这项研究中,我们使用了单侧缺氧缺血(HI)小鼠模型。$$text{ER}alpha$ +/+或$$text{ER}alpha$ -/-小鼠在出生后第9天(P)遭受HI,HI后小鼠接受车辆对照或TrkB激动剂DHF治疗7天。小鼠成年后,我们使用新物体识别、新物体定位和开阔地测试来评估长期记忆和焦虑样行为。然后用免疫组化方法评估小鼠大脑的组织损伤情况。新生儿DHF治疗可防止HI诱导的雌性小鼠成年后识别记忆和定位记忆的衰退,但雄性小鼠却没有这种效果。缺乏$text{ER}alpha$$的雌性小鼠没有这种保护作用。新生儿HI后,DHF疗法可改善雌性成年期的识别和定位记忆结果,但这两种结果分别倾向于或依赖于$text{ER}alpha$。有趣的是,只有在缺乏$text{ER}alpha$的小鼠中,DHF才会引发雌雄小鼠的焦虑样行为。当我们评估损伤的严重程度时,我们发现DHF疗法并没有降低组织损失的百分比与功能恢复的比例。此外,我们还观察到,$text{ER}alpha$的存在显著降低了HI相关的男女总死亡率。这些观察结果为DHF的治疗作用提供了证据,其中TrkB介导的雌性识别记忆和位置记忆的持续恢复分别与$text{ER}alpha$有关和依赖于$text{ER}alpha$。然而,DHF疗法的有益效果并不包括减少组织的总损失,而可能来自于以细胞特异性方式增强残余组织的功能。众所周知,新生儿大脑的低氧输送和低血流量时期会对其成年后的认知能力造成终身损害。有趣的是,男性新生儿比女性更容易受到这种损伤。造成这种性别差异的机制尚不清楚。在这里,我们测试了神经生长因子受体酪氨酸激酶 B(TrkB)在小鼠新生儿缺氧缺血(HI)后提供长期神经保护中的作用。我们以前的研究表明,当小鼠在新生儿缺氧缺血后几天内接受 TrkB 激动剂 7,8-二羟基黄酮(DHF)治疗时,只有雌性小鼠能获得短期神经保护,而且这种保护依赖于雌激素受体 alpha 受体($$text{ER}alpha$$)的存在。在这项研究中,我们通过让有或没有雌激素受体α受体的小鼠接受HI来扩展这些观察结果。其中一些小鼠在HI后立即接受了DHF治疗。成年后,我们对小鼠的记忆力和焦虑行为进行了测试。测试结束后,我们对小鼠的大脑组织损失进行了评估。我们的研究结果表明,新生小鼠在HI后接受DHF治疗,成年后只有雌性小鼠的记忆力得到了保护,而且这种效果依赖于$text{ER}alpha$$的存在。 此外,DHF治疗会引发缺乏$text{ER}alpha$的小鼠的焦虑样行为。我们还发现,这种神经保护并不依赖于损伤后脑组织的保存。这些结果让我们对新生儿时期雌性对缺氧缺血性发作的抵抗力背后的机制有了更深入的了解。
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引用次数: 0
期刊
Biology of Sex Differences
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